Activation of the anti-cancer agent upamostat by the mARC enzyme system.

Upamostat (Mesupron®) is a new small molecule serine protease inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b₅ and NADH cytochrome b₅ reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat.

Citation

Danilo Froriep, Bernd Clement, Florian Bittner, Ralf R Mendel, Debora Reichmann, Wolfgang Schmalix, Antje Havemeyer. Activation of the anti-cancer agent upamostat by the mARC enzyme system. Xenobiotica; the fate of foreign compounds in biological systems. 2013 Sep;43(9):780-4

PMID: 23379481

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